SO-16 FIRE-4 (AIO-KRK-0114): Randomized study for a switch maintenance concept with 5-FU plus bevacizumab after induction treatment with FOLFIRI plus cetuximab versus continued treatment with FOLFIRI plus cetuximab – secondary endpoint
Authors: V. Heinemann, L. Fischer von Weikersthal, M. Fuchs, F. Kaiser, K. Heinrich, D. Modest, R. Hofheinz, T. Decker, A. Gerger, S. Angermeier, H. Rumpold, A. Dickhut, L. Öhler, B. Grünberger, D. Niedersüß-Beke, M. Sandmann, S. Kasper, G. Prager, S. Stintzing
Journal: Annals of Oncology (2022)

FIRE-4 (AIO KRK-0114) is performed in RAS-wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. In this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued every 2 weeks until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) every two weeks until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. The present analysis investigates the impact of sidedness on study results. From August 2015 to January 2021, 672 patients were randomized and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). The primary analysis of the overall study population demonstrated comparable outcome data in both treatment arms. Among 643 patients evaluable for sidedness, 84% (n=539) presented with left-sided tumors and 16% (n=104) with right-sided tumors. In left sided tumors comparable results were obtained in both treatment arms (A vs B) with regard to ORR (78.8% vs 78.0%), PFS (11.5 months vs 11.6 months), and OS (33.2 months vs 35.6 months). In right-sided tumors, efficacy data (arms A vs B) were generally less favorable. ORR was numerically superior with continued application of cetuximab in arm A (56.8% vs 42.2%, P=0.27). However, survival data appeared to be more favorable in the switch maintenance arm (B) with regard to PFS (5.5 months vs 7.4 months, P=0.38) and OS (12.5 months vs 21.2 months, P=0.27). FIRE-4 confirms the efficacy of FOLFIRI plus cetuximab as first-line treatment of patients with RAS wild-type mCRC. In patients with left-sided tumors, continued application of cetuximab induced comparable efficacy as an early switch from FOLFIRI cetuximab to maintenance therapy with 5-FU plus bevacizumab. While in right-sided tumors, differences in outcome did not reach the level of statistical significance, survival data are numerically in favor of the bevacizumab switch-maintenance arm.